Prof. Lizhe ZHU published an article in Proceedings of the National Academy of Sciences


The collaborative research led by Professor Lizhe ZHU, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Professor REN Ruobing, Fudan University, and Professor Arieh WARSHEL, 2013 Nobel Laureate in Chemistry, published their paper entitled "Fine-tuning activation specificity of G-protein-coupled receptors via automated path searching" in Proceedings of the National Academy of Sciences(PNAS). The co-first author are Dr. RU Juan and Dr. PANG Bin.
Significance
G-protein-coupled receptors (GPCRs) are the targets for ~35% of Food and Drug Administration-approved drugs. Yet designing selective GPCR agonists remains challenging, because it requires a thorough understanding of the activation mechanism of several GPCRs by various ligands. Molecular dynamics simulations can offer fine details of activation but suffer from low efficiency. To tackle this efficiency bottleneck, we present an automated input-free protocol, built upon the travelling-salesman automated path searching (TAPS). Our approach not only dissected the activation of Sphingosine-1-phosphate receptors (S1PRs) by existing agonists for treating autoimmune diseases but also enabled the design of a unique compound that activates S1PR1 exclusively. This mechanism-based design minimized wet-lab costs through three computational iterations and a single synthesis of the final compound.
Abstract
Physics-based simulation methods can grant atomistic insights into the molecular origin of the function of biomolecules. However, the potential of such approaches has been hindered by their low efficiency, including in the design of selective agonists where simulations of myriad protein–ligand combinations are necessary. Here, we describe an automated input-free path searching protocol that offers (within 14 d using Graphics Processing Unit servers) a minimum free energy path (MFEP) defined in high-dimension configurational space for activating sphingosine-1-phosphate receptors (S1PRs) by arbitrary ligands. The free energy distributions along the MFEP for four distinct ligands and three S1PRs reached a remarkable agreement with Bioluminescence Resonance Energy Transfer (BRET) measurements of G-protein dissociation. In particular, the revealed transition state structures pointed out toward two S1PR3 residues F263/I284, that dictate the preference of existing agonists CBP307 and BAF312 on S1PR1/5. Swapping these residues between S1PR1 and S1PR3 reversed their response to the two agonists in BRET assays. These results inspired us to design improved agonists with both strong polar head and bulky hydrophobic tail for higher selectivity on S1PR1. Through merely three in silico iterations, our tool predicted a unique compound scaffold. BRET assays confirmed that both chiral forms activate S1PR1 at nanomolar concentration, 1 to 2 orders of magnitude less than those for S1PR3/5. Collectively, these results signify the promise of our approach in fine agonist design for G-protein-coupled receptors.


Link to the article
https://doi.org/10.1073/pnas.2317893121